Vascular and metabolic diseases are, despite cancer, the leading causes of death in the western world. Although many different ways of treating vascular and metabolic diseases are known, there is still a need for improved medication. Life-style modifications and drug therapy can decrease and delay the morbidity and mortality associated with these diseases. Treatments which have been proven to reduce the risk for morbidity and mortality in vascular diseases have been typically shown to either improve impaired vascular function or to delay/prevent the progression of vascular dysfunction caused by hypertension, atherosclerosis or other classical metabolic risk factors. Examples for such treatments are calcium channel blockers, beta blockers, angiotension-enzyme converting inhibitors or angiotension receptor blockers.
In patients with coronary artery disease (CAD) due to atherosclerosis, who are suffering from angina pectoris, one of the established standard treatments involves treatment with organic nitrates, specifically nitrate esters, such as glyceryl trinitrate (nitroglycerine), isosorbide dinitrate, or pentaerythrityl tetranitrate, which act all as coronary vasodilators and improve symptoms and exercise tolerance. Most organic nitrates (e.g. mononitrates and trinitrates) are fast acting pharmaceuticals with a relatively short halflife and have the typical disadvantage that patients develop a nitrate tolerance, meaning that part of the pharmacodynamic effect is lost during chronic treatment and a three times daily dosing regimen.
An important group of pharmaceuticals for the treatment of vascular diseases, in particular for patients suffering from hypertension and/or chronic heart failure and concomitant metabolic disease, but not limited to these conditions, are angiotensin II receptor blockers. The antihypertensive activity is due mainly to selective blockade of AT1 receptors and the consequent reduced pressor effect of angiotensin II. Angiotensin II causes potent vasoconstriction, aldosterone secretion and sympathetic activation. All of these actions contribute to the development of hypertension. There are several marketed compounds of this class, in particular losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan. With the exception of telmisartan, they all comprise a tetrazole structural unit. Several clinical trials have demonstrated that angiotensin II receptor antagonists are as effective as calcium-channel blockers, beta-blockers, and ACE inhibitors in the treatment of hypertension and induce fewer adverse effects. Valsartan is first described in U.S. Pat. No. 5,399,578.
Nitrate esters of drugs in general are described in WO 00/61357. Particular nitrate esters of valsartan derivatives are described in WO 2005/011646 and WO 2007/019448. Diazeniumdiolate derivatives have recently been recognized as alternatives for nitrate esters, setting free two molecules of NO under physiological conditions. A diazenium-diolate derivative of tacrine is described by L. Fang et al., J. Med. Chem. 51, 7666-7669 (2008).